CA1258874A

CA1258874A - Process for the resolution of a racemate

Info

Publication number: CA1258874A
Application number: CA000495417A
Authority: CA
Inventors: Alan E. Comyns; Gareth W. Morris; John P. Sankey
Original assignee: Laporte Industries Ltd
Current assignee: Evonik LIL Ltd
Priority date: 1984-11-17
Filing date: 1985-11-15
Publication date: 1989-08-29
Also published as: ES548893A0; EP0182170A2; FR2573326A1; GB2167052B; IT8548796A0; EP0182170A3; EP0182170B1; DE3540283A1; NL8503042A; BE903653A; US4622214A; AU572439B2; GB8526571D0; AU4974485A; ES8705835A1; CH668561A5; GB2167052A; FR2573326B1; US4687871A; JPS61183116A

Abstract

- ? -ABSTRACT

A process for the Resolution of a Racemate A racemate may be resolved into its enantiomers by stereoselective adsorption on a crystalline molecular sieve having an assymetric crystal structure for example zeolite ZSM11. The resolution may be assisted by the presence of an enantiomer of a compound separable from that of the racemate either preadsorbed on the molecular sieve or included in a polar solvent solution of the racemate to be treated.
Resolution of an alkyl aryl sulphoxide racemate is exemplified.

Description

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A Process for the Resolution of a Racemate This invention relates to the resolution oP a racemate into its optically active enantiomers.
Many compounds which play significant roles in biological processes do so in their naturally occurring enantiomeric forms. Synthetic routes to these compounds often produce the racemate and require lengthy and expensive modiPication to produce separate enantiomers. As a result ~ynthetic enantiomers for use in biochemical research or development, for example ~or the production oP
pharmaceuticals, or chemotherapeutic agents, vitamins or hormones, command market prices vastly in excess oP those of the corresponding racemates.
One group of compounds to which the above described situation applies are the alkyl aryl sulphoxides, such as methyl paratoluene sulphoxide usable in one enantiomeric form in ~he ~ynthesis of both maytansine, an antitu~our ard chemotherapeutic material, and vikamin E talpha-tocopherol).
Attempts have been made to re~olve racemates by stereo~elective adsorption onto a solid urPace. It has been suggested that optically asymmetrical cry~tal surface~, such as that of d- or l- quartz, may be ePfective stereo~elective adsorbents. Unequivocal affirmative results have apparently not been obtained, however, in view oP the ~tatement by Professor R.D~ Gillard (Chemistry in Britain Nov 1984, pages 1022-1Q24) that rotational results, apparently ~howing stqreosp~cific ad~orption, may be lZ58~

- 2 - 051WF CS
spurious since they may readily be caused by processing techniques, particularly by inefficient filtration leaving ultramicroscopic particles suspended. At any rate, no practical process for the resolution of racemates based on the surface adsorption properties of optically active quartz or any other inorganic material has been described.
It is now realised, according to the invention, that certain crystalline molecular sieve materials are crystallographically assymetrical and also that this assymetry is reflected in the morphology of their internal pore structure so as to render them usable for the resolution of racemates into their constituent enantiomers.
This property is hereafter called "chiral" activity.
According to the present invention there is therefore provided a process for the resolution of a racemate by stereoselective adsorption on a solid adsorbent characterised by the use of a crystalline molecular sieve material having an asymmetrical crystal structure as the adsorbent. Preferably the racemate is treated in the liquid or vapour form or as a solution of or containing an organic, particularly preferably a polar organic, solvent. According to one aspect of the invention the contact is conducted in the presence of a "distinct" enantiomer by which is meant an enantiomer of a compound chemically and/or physically distinat from and there~ore separable from the racemic compound or its enantiomers.
By the term "molecular sieve" is meant a material containing pores of a size which will accept molecules below a certain size thereby enabling said molecules to be '~ieved' or separated from larger molecules. Typically in zeolite molecular sieves the pores are from about 2 Angstroms to about 20 Angstroms in diameter.
The molecular sieves preferred to use according to this invention are for example, but not exclusively, those based on three dimensional silica frameworks such as silicalite, or the aluminosilicates and other metallosilicates collec~lvely referred to a~ "zeolites" or the ~-2~ ~ ~7~

_ 3 - 051WF CS
aluminophosphates. Due to their physical and chemical stability an~ their high internal surface area of specifically sized channels such materials have proved ideally suited to use in industrial adsorptive processes.
The molecular sieve material may also be derived by the removal of residual templates from aluminophosphate molecular sieves such as those described in U.S. Patent No.
4310440 which have the general formula Al203 1.0 +/- 0.2 P20s and contain uniform pores having dimensions of from about 3 to about 10 Angstroms.
The molecular sieve material may also be derived by the removal of residual template from the so-called organosilicates described in US Patent No. 3941871 which are essentially silica framework materials containing less than a small proportion of alumina and a small proportion o~
template derived organic cations.
The molecular sieve material may also be selected from the silica polymorphs described in U.S. Patent No. 4073865.
In crystallography it is recognised that there are 11 "enantiomorphous" and 4 "non-enantiomorphous" point groups in which crystal asymmetry can exist. These are summarised in Table I.
~able I
.
Systel~ Point Groups Enantiornorphous Non-enantiomorphous Triclinic Monoclinic 2 m Orthorhombic 222 mm2 ~etragonal 4 422 4 42m Trigonal 3 32 Hexagonal 6 622 Cubic 23 432 By utilising techniques known in the art of crystallography, ~or example as summarised in the book "Elementary Crytallography" by Martin J Buer~er, published by MIT Press 1963 in the chapter entitled "Practical determination o~ point group symmetry" and by x-ray powder di~frac~ion and nuclear magnetic resonance studies crystalline molecular ~ieve material~ such a~ zeolites may i8~7~
_ 4 _ 051WF CS
be allocated to their appropriate symmetry groups. Those which fall within the 15 point groups set out in Table I may be used in the practice of this invention. By way of example the point groups, and the appropriate space group within each point group, for certain microporous aluminosilicates are set out in Table II.
Table II
Zeolite Channel Symmetry Dimensions - Point Space Group Group Bikitaite 3.2x4.9 2 P21 Li20 . A1203 . 4si02 2H20 Edingtonite 3.5x3.9 222 P2l212 BaO.Al2O3.3si2~4H2O
Harmotome (4.2x4.4)(2.8x4.8)(3.3) m Cm BaO.Al2O3.6siO2 6H2o Cancrinite 6.2 6 P63 Na6A16Si6024CaC032H2 Heulandite (4.0x5.5)(4.4x7.2)~1x4.7) m Cm CaO.Al203 Laumonite 4.6x6.3 m Am CaO.Al2O3 4siO2 4H2o Scolecite 2.6x3.9 m Cc CaO.Al203.3SiO2~3H2o Thomsonite 2.6x3.9 mm2 Pnn2 (Na2Ca).O.Al2O3.2SiO2.2.4H2O
Yugawaralite 3.6x2.8 m Pc CaO.Al2O3.6siO2~4H2o Natrolite 2.6x3.9 mm2 Fdd2 Na2O.Al2O3.3SiO2 2H2O
Amongst the synthetic molecular sieves the aluminosilicate ZSM11, identified fully in British Patent Specification No. 1339501, is allocated to tetragonal non-enantiomorphous point group ~2m (Wature 1978 Vol 275 page 119) ? as is it~ silica analo~ue "Silicalite-2" ~Nature, Vol 28q, 23 August 1979 page~ 664-5 and US Patent No. 4Q73865 referred to above). The aluminosilicate ~ ~S 8 ~ ~

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Theta I, identified fully in European-Patent Publication No. 0057049, is allocated to space group Cmc2, which is derived from orthohombic non-enantiomorphous point group mm2 (Nature, Vol 312, 6 Dec 1984. pages 533-534). Without limiting the scope of the invention in any way thereto, the use of the zeolite ZSM11, Theta I or Silicalite 2 is therefore particularly provided according ko the present invention. While naturally occurring materials are not excluded it is preferred for reasons of purity that they be synthetic. This need not limit the variety of materials available since new synthetic zeolites, and synthetic analogues of naturally occurring zeolites, are constantly being produced. The asymmetric natural zeolite edingtonite was synthesised as long ago as 1974 (Barrer et al; J. Chem.
Soc. (Dalton) 1974, pages 934-41).
The channels or cavities of opposite symmetry in asymmetrical molecular sieve materials apparently show discriminatlon between the appropriate enantiomers of a racemate. It is thought that the distinct enantiomer ma~ be ad~orbed preferentially into those channels in an asymmetrical molecular sieve material which are appropriate to its symmetry, as shown by its optical form, leaving other channel~, appropriate to the opposite optical form, to be occupied preferentially by the appropriate enantiomeric component of the racemate, the remaining enantiomeric componert of the racemate being consequently less strongly adsorbed, and being separable on the basis of this difference.
~Jhile the presence of the distinct enankiomer would be

3~ expected to result in some degree o~ concentration of the enantiomer of opposite optical form in solution recovered from the molecular sieve material irrespective of its ab~orption affinity for the molecular sieve it is preferred, ~or optimum performance, that the distinct enantiomer be of a compound which is more s~rongly adsorbed thereon than the compound o~ the racemate~ ~elative adsorption affinities are readily e~tablished by simple absorption tests carried ~2~;8 517~
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out on solutions o~ tne compounds in question followed by analysis of the eluate.
The invention may be put into practice by various operational procedures involving contacting the racemate, in liquid form or in solution, with a bulk of the adsorbent and recovering one or more fractions of the contacted racemate, relatively concentrated or depleted in one of the enantiomers, from the adsorbent and if desired recycling the one or more fractions to enhance that concentration or depletion.
According to one procedure the asymmetric molecular sieve material is first contacted with a solution of the distinct enantiomer so that it absorbs a quantity of that enantiomer, and is separated from the residue of that solution and the molecular sieve material is then contacted with a solution of the racemate whereupon it tends to adsorb one of the enantiomeric components preferentially, and is separated ~rom the residue of that solution and the adsorbed solution enriched in one enantiomeric component o~ the racemate is recovered ~rom the molecular sieve material and may be recycled to further enrich it in the said enantiomeric component. The other enantiomeric component may be separated from the residual racemate solution and from any distinct enantiomer which may be present or may be recycled to further increase the concentration o~ the other enantiomeric component therein. The distinct enantiomer may also be recycled.
According to a further procedure, which is particularly adaptable to continuous or semi-continuous operation, the distinct enantiomer is included with the solutlon of the racemate and the molecular sieve material is contacted with the resulting mixture. It has been found that i~ the solution containing the distinct enantiomer and the racemate is pas~ed through a bed o~ the molecular sleve material the ef~ect of the pre~ence of the di~tinct enantiomer is to retard one of the enantiomeric constituents of the racemate thereby producing an effluent having a differential 8~
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concentration of the said enantiomeric constituents with time. The recovery of fractions of eluate and recycling procedures will progressively increase this differential providing the basis for a practical resolution process.
Again, the distinct enantiomer can be removed from fractions rich in it b~ known chemical or physical separation techniques and recycled.
The selection of a distinct enantiomer and indeed the selection of a racemate for use or treatment according to this invention is preferably made on the basis of its molecular size, polarity and polarisability. It is well known that molecular sieves such as zeolites can often adsorb molecules having theoretical dimensions somewhat larger than the pore size of the molecular sieve although said average dimension is preferably not more than 3 Angstroms particularly preferably not more than 2 Angstroms and, for example) very suitably not more than 1 Angstrom greater than the greatest pore diameter and the selection of the di3tinct enantiomer and of the racemate is pre~erably made on this basis. Molecule~ which are substantially smaller than the said pores may tend to pass through the molecular sieve without attaining a sufficiently intimate relationship with the internal structure of the molecular sieve to ~ive a sufficiently marked resolution ef~ect.
Preferably the distinct enantiomer and the racemate have an average molecular dimension at least equal to one third, particularly preferably to one half for example very suitably to three quarter~ of the minimum pore diameter.
The pore diameter of particular molecular sieves is well known. For example, that of zeolite ZSM11 and of its silica analogue Silicalite II is in the approximate range 5.3-6.3 Angstroms. Preferably the enantiomer is such that it passes through the said material but less readily than the racemat~. It may be that different molecular sieve materials, particularly the ~ynthetic molecular ~ieve materials preferred in the practice of this invention will, apart from the ~ffect o~ pore siæe, have di~ferent 51~7~

a~finities for the same compound so that trials with the molecular sieve material of choice may be advantageous to determine the particular enantiomer to be used or the molecular sieve to b used to treat a particular racemate.
This is well within the ordinary skill in the art relating to molecular sieve usage. Such a selection technique will enable the invention to be applied to new molecular sieve materials having asymmetry, or known molecular sieve materials which are found to have asymmetry.
If the molecular sieve ma~erial is itself enantiomeric the use of a distinct enantiomer may be unnecessary ar,d, according to the invention, the solution of the racemate may merely be passed through a bed of the molecular sieve material or otherwise contacted with it, to achieve resolution.
The distinct enantiomer may be selected from enantiomers of any suitably sized compounds having optical activity. Very suitably the enantiomer may be an amine for example a suitable amino acid such as proline, or a suitable heterocyclic nitrogen containing compound such as a piperidine or a quaternary ammonium salt thereof, for example 3-methyl piperidine or 3-methyl N.N. dimethyl piperidinium bromide or a suitable alicyclic compound ~or example alpha pinene or a suLtable aliphatic alcohol for example 2-methyl butanol. Preferably, the distinct enantiomer is selected from ~uitable cobalt complexes, particularly preferably complexe~ with relatively small organic ligands containing, ~or example, not more than 4 carbon atoms. Pre~erably the organic ligand may be an amine. One example of a suitable cobalt~3 complex i~ the bis(ethylene diamine) complex.
~ he solutions of the racemate or of an enantiomer referred to above are preferably in an organic solvent. The organic ~olvent preferably includes a polar ~olvent in at least 5% particularly preferably at lea~t 25~ by volume in a non~polar solvent or consists of a polar solvent. An example of a ~uLtabl~ polar solYent i~ met~anol and an 8 ~ ~

example o~ a suitable non-polar solvent is hexane.
While the present invention may be applicable to the production of directly biochemically useful enantiomers, if such may be adsorbed within a given asymmetrical molecular sieve, its main utility may be in the production of relatively small enantiomer molecules which are therefore more suited to adsorption within the normal channel size range of from about 3 to 15 Angstroms, of known zeolite molecular sieves.
A current approach to the production of enantiomeric biochemically useful materials is the "chiron" approach whereby the synthesis is based on the use of small highly functional chiral "synthons" such as, for example, ~-phenyl-ethanol, epichlorhydrin, methyl p-toluene sulphoxide, 4-bromo 192-epoxy butane, propylene oxide, 2 chlorobutane and 2-aminobutane. The synthesis of even these simple molecules in enantiomeric form is time-consuming and laboriou~ and the provision o~ the present process ~or the adsorptive resolution of the racemates is potentially of great benefit.
The present invention will now be illustrated by reference to the following Examples. Examples 1-3, 5 and 8 are according to the invention. Example 4, 6, 7 and 9 are inserted for comparative purpo~es on~y.
Examples 1-3 Resolution of (~/-)-1-phenylethanol racemate.
The proportion of (~) and (-) enantiomers in a - l-pheylethanol racemate was measured before and after being treated according to the invention, by high pressure liquid chromatography on a BAKERBOND DNBPG (Trademark) chiral column o~ J.T. Baker Research Products. The stationary phase was an enantiomer of N-3,5-dinitrobenæoyl-phenylglycine bonded coYalently to a 5-micron aminopropyl silica. The mobile phase was 99.5~ n-he~ane and 0.5~ isopropyl alcohol. Detec~ion was by UVabsQrbance at 254 nrn.
A 5 g ~ample o~ ~eolite ZSMl1, produ¢ed accordin~ to ~2~ 37~
.

United States Patent No. 3832449 was immersed in 25 ml of a 1% by volume solution of (+) - phenylethylamine in n-hexane allowed to stand overnight, removed, filtered and air dried.
The sample of zeolite was then immersed in 25 ml of a 1% by volume solution of the 1-phenyl-ethanol racemate in 99.5% by volume n-hexane and 0.5% by volume toluene. Over a period of 7 hours samples of the racemate were removed periodically and the ratio of each enantiomer to toluene determined by high pressure liquid chromatography using the method as above. Over the 7 hour period the proportion of one enantiomer in t.he samples dropped by 3.7% and the other by 6.6~.
Further tests were carried out on the resolution of (+/-)-1-phenyl ethanol using ZSM11 molecular sieve loaded with (-)-2-methyl butanol (Example 2) or (+)-alpha pinene (Example 3). In both Examples a clear alteration of the proportion of the enantiomers of the 1-phenyl ethanol was obtained compared with no alteration when the 1-phenyl ethanol was pas~ed through unloaded zeolite ZSM11.
Example 4 Example 1 was repeated using the symmetrical zeolite ZSM5 produced according to United States Patent No. 3702886.
No change in the ratio of enantiomers in the racemate was detected.
Example 5 Resolution o~ methyl phenyl sulphoxide raaemate.
The proportion o~ (+) and (-) enantiomers in a methyl phenyl sulphoxide racemate was measured before and a~ter being treated according to the invention by gas chromatography on a 25 m CHI~ASIL-V~L (Trademark) chiral capilliary column supplied by Applied Science. The skationary phase was an enantiomer o~ valine-t-butylamide coupled ~o a dimethylsiloxane/carboxyalkylMethylsiloxane copolymer.
A skainless skeel column 30 cms long and 0.6 cm out3ide diameter wa~ packed with the zeolite ZSM11. A ~olvent m1xkure consiskin~ o~ a volume ratio o~ 45 n-hexane, 35 7~

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methanol and 10 isopropyl alcohol was pumped through the column at a rate o~ 1 ml per minute. 10 microlitres of a dilute solution of methyl phenyl sulphoxide racemate in the same solvent was introduced into the solvent and was found to elute without any alteration in the ratio of its enantiomers. The solvent mixture being pumped through the column was then adjusted in composition to a volume ratio of 45 n-hexane, 44 methanol, 11 isopropyl alcohol with 0.5 g of a proline enantiomer. The same quantity of methyl phenyl sulphoxide racemate as used above was added to the adjusted solution. Based on peak areas the ratio of the enantiomers of methyl phenyl sulphoxide in the eluate was found to alter with time from 48.5:51.5 through 47.6:52.4 to 44.4:55.6.
Examples 6 to 9 The equipment was set up with four small stoppered vessels. Two (Examples 4 and 5) contained a natural calcium montmorillonite clay having a cation exchange capacity of , 76 m eq/100 g (available from Laporte Industries Limited as "Surrey Powder") (2g) and two contained synthetic zeolite ZSM11 (lg) (Examples 6 and 7). The bulk clensity of the montmorillonite was greater than that of the ZSM11 and the different weights compensated for this.
5 ml of a solution containing 103 micro-moles (~)-bis(ethylenediamine)cobalt(III) bromide demineralised water were added to one of thq montmorillonite samples (Example 4) and one of the ZS~l11 samples (Example 6). 5 ml of demineralised water was added to the other two samples.
Each of the ~our samples was then treated with 5cm3 of a solution contalning 165 micro-moles of methyl phenyl sulphoxide in methanol.
The four samples were then left to stand for two days, with occasional shaking, to equilibrate. The supernatant liquids were then drawn of~ and analysed to give the re~ults in Table III. Analy3is was by capillary gas chromatograp~ly using a 25 m 'Chirasil-Val' column. The gas chromatography conditions were as follows :-.
Injector 1?QC Detector 140C
,d e, J`~

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, .

Initial oven temperature 80C for 1 minute, then linear temperature programmed to 120C at 4C per minute. The two enantiomers elute after 10.2 and 10,5 minutes.
Table III

Example (+)- METHYL PHENYL (-) METHYL PHENYL RATIO
SULPHOXIDE AMOUNT SULPHOXIDE AMOUNT (~)/(-) SORBED/micro-moles SORBED/micro-moles 6 19.3 28.8 1.49 7 53.8 55.5 1.03 8 17.4 40.8 2.34 9 ll5.7 45.6 ~.00 STANDARD SOLUTION
OF METHYL PHENYL 82.5 82.5 1~00 SULPHOXIDE

The data in Table III shows that the use of the .:
molecular sieve material according to the invention (Example 8) giV9S a considerably more effective resolution than the layered clay mineral material (Example 6).

3o ;

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the resolution of a racemate of a compound by stereoselective adsorption on a solid adsorbant characterised by the use of a crystalline molecular sieve material having an asymmetrical crystal structure as the adsorbant.

2. A process as claimed in claim 1 wherein the racemate in liquid form or as a solution is contacted with a bulk of the adsorbant and one or more fractions of the so contacted racemate relatively concentrated or depleted in one of the enantiomers thereof, are recovered from the adsorbant.

3. A process as claimed in claim 2 wherein said one or more fractions are recycled to further contact with the bulk of adsorbant thereby to enhance said depletion or concentration.

4. A process as claimed in claim 1, 2 or 3 wherein the racemate is in the form of a solution comprising a polar organic solvent.

5. A process as claimed in claim 1, 2 or 3 wherein the adsorbant is in contact with a distinct enantiomer of a compound separable from that of the racemate.

6. A process as claimed in claim 1, 2 or 3 wherein the adsorbant is in contact with a distinct enantiomer of a compound separable from that of the racemate, and further characterised in that the molecular sieve material is first contacted with a solution of the distinct enantiomer and is separated from the residue of that solution and is then contacted with the solution of the racemate and is separated from the residue of that solution, and adsorbed solution, containing an increased proportion of one enantiomeric constituent of the racemate, is recovered from the molecular sieve material.

7. A process as claimed in claim 1 wherein the adsorbant is in contact with a distinct enantiomer of a compound separable from that of the racemate, and further characterised in that the mole-cular sieve material is contacted with a solution of racemate compound and of the distinct enantiomer.

8. A process as claimed in claim 7 wherein the solution is passed through a body of the molecular sieve material and separate fractions of an eluate containing differing ratios of the enantio-meric constituents of the racemate and of the distinct enantiomer therefrom are recovered therefrom.

9. A process as claimed in claim 8 wherein the distinct enantiomer is recovered from at least some of the fractions and recycled.

10. A process as claimed in claim 8 or 9 wherein fractions containing an increased proportion of one enantiomeric constituent of the racemate, relative to the other, are recycled to further increase said proportion.

11. A process as claimed in claim 1, 2 or 3 wherein the crystalline molecular sieve material having an asymmetrical crystal structure comprises a three dimensional silica framework.

12. A process as claimed in claim 1, 2 or 3 wherein the crystalline molecular sieve material having an asymmetrical crystal structure comprises a three dimensional silica framework and the molecular sieve material is a zeolite.

13. A process as claimed in claim 1, 2 or 3 wherein the crystalline molecular sieve material having an asymmetrical crys-tal structure comprises a three dimensional silica framework, the molecular sieve material is a zeolite and the zeolite is ZSM11, Silicalite 2, or Theta I.

14. A process as claimed in claim 1, 2 or 3 wherein the distinct enantiomer is an entantiomer or proline of l-phenyl-ethyl-amine.

15. A process as claimed in claim 1, 2 or 3 wherein the distinct enantiomer is an enantiomer of a cobalt complex.

16. A process as claimed in claim 1, 2 or 3 wherein the distinct enantiomer is an enantiomer of a cobalt complex and the ligand forming the complex is an amine containing not more than 4 carbon atoms.

17. A process as claimed in claim 1, 2 or 3 for the resolution of a racemate of an alkyl aryl sulphoxide.

18. A process as claimed in claim 1, 2 or 3 for the resolution of a racemate of an alkyl aryl sulphoxide wherein the sulphoxide is a 1 to 4 carbon alkyl substituted, or a 6 carbon cycloalkyl substituted phenyl sulphoxide.